This Program is uniquely based on a large-scale analysis of human joint aging and supported two major biomedical research centers TSRI and UCSD. A multi-disciplinary approach has been established that includes histomorphometry, cell and molecular biology, biochemistry, biomechanics and genomics as basic science disciplines and orthopaedics and rheumatology as the relevant clinical specialties. The overall hypothesis proposes that normal joint aging is distinct from osteoarthritis (OA) and that a combination of risk factors in the context of aging-associated changes in cells and extracellular matrix trigger the joint remodeling process that generates clinical symptoms and characteristic OA pathology. The proposed Program will continue the existing Cores (A: Administration; B: Tissue; C: Morphology). The following five Projects are proposed: Project 1: Chondrocyte Growth and Death in Aging (M. Lotz) This Project will address the occurrence and significance of chondrocyte apoptosis. Aging-associated changes in cell cycle regulators that account for decreased cell proliferation and aging-associated changes in chondrocyte gene expression and cell survival will be analyzed. Project 2: PPi Metabolism and Chondrocalcinosis (R. Terkeltaub) The hypothesis proposes that co- ordinate changes in expression and localization of PC-1, a PPi generating enzyme, and ANK, a PPi membrane channel occur in aging. The role of Cartilage Intermediate Layer Protein (CILP) that has been suggested to generate PPi, will also be addressed. Project 3: Molecular Mediators of Chondrocyte Function in Aging and OA (D. Amiel) The Project will index the expression of catabolic and anabolic mediators in an aging rabbit model of OA and human joints. In extension of prior studies PTHrP and TGF6 will be evaluated in a model of osteochondral defect repair. Project 4: Collagen Network Failure in Cartilage Aging and OA (R. Sah) The Project will analyze biomechanical depth-dependent properties of human articular cartilage and investigate if cell density, organization, and phenotype are altered in aging and OA. Project 5: Genetic Misregulation in Cartilage Aging and Osteoarthritis (P. Schultz) The Project will test the general hypothesis that mitotic misregulation is a key determinant in chondrocyte aging. Transcript profiles of chondrocytes, in normal and OA cartilage are obtained. The second phase of this Project will focus on functional analyses Collectively, the proposed Program will identify genetic changes that determine joint aging and thus define new molecular markers for diagnosis and targets for prevention and therapeutic intervention.